Mithridion, Inc. - Breaking new ground in drugs for Alzheimer's disease and schizophrenia

Mithridion's Subtype Selective Muscarinic Agonist Platform

Clinical Experience with Muscarinic Agonists

Alzheimer’s Disease
Several muscarinic agonists have been tested in patients with Alzheimer’s disease (AD), principally in the early- to mid-1990s. In Phase II clinical trials, Lilly’s xanomeline had beneficial effects on disease symptoms in AD (Bymaster, Whitesitt, and others, "Xanomeline, a selective muscarinic agonist for the treatment of Alzheimer's disease", Drug Dev Res (1998), 4, 158 - 170). Talsaclidine (Hock, C et al, Ann NY Acad Sci 2000; 920: 285-91) and AF102B (Nitsch, RM et al, Ann Neurol 2000; 48: 913-8) also reduced the concentration of the neurotoxic peptide, Aβ, in the cerebrospinal fluid, suggesting that subtype selective agonists might be effective in slowing down the disease processes and preventing neuron loss. The first generation drugs thus validated this therapeutic approach but unacceptable adverse events and side effects were seen including muscarinic effects such as sweating, salivation, diarrhea, and fainting, which ultimately led to their abandonment. Several of these drugs were subsequently shown to have very low partial agonist efficacy in vivo (Bymaster, FP et al, Brain Res 1998; 795: 179-190), suggesting that efficacy was an issue. Xanomeline was excessively metabolized, leading to low bioavailability and pharmacologically active metabolites that might have contributed to side effects. This also required the use of high oral doses, possibly contributing to adverse muscarinic side effects in the GI tract. It is now clear that the first generation drugs were neither as active nor as selective as originally thought.

Schizophrenia
Results of early trials of xanomeline, a first generation subtype selective muscarinic agonist, provided proof-of-concept of this hypothesis in a Phase II trial in schizophrenia (Shekar, Potter and others, “Selective muscarinic agonist xanomeline as a novel treatment approach for schizophrenia”, Am J Psych . Subjects in the xanomeline group showed improved performance in cognitive tests. Xanomeline had previously demonstrated antipsychotic effects in animals. (Mirza, Peters and others “Xanomeline and the anti-psychotic potential of muscarinic receptor subtype selective agonists”, CNS Drug Rev (2003), 9, 159-186).